Warfarin is a vitamin K antagonist used as an anticoagulant used for treatment and prevention of a variety of coagulopathic and thromboembolic disorders. While it was initially marketed as a rodenticide, it has been used as a medication for more than a half-century. Additionally, superwarfarins are now also used as pesticides and should be considered as agents that may cause potential “warfarin toxicity” and have been noted to be one hundred times as potent compared to warfarin.
Toxicity can be thought to occur in a variety of methods: 1) Intentional adult overdose; 2) Unintentional overdose/toxicity, and 3) pediatric ingestion. The intentional overdose may be the most obvious, though has been noted to be “relatively rare,” with one 25-year survey of two tertiary centers with toxicology services having a total of 22 non-pediatric intentional overdoses. Unintentional overdose or toxicity can occur through various mechanisms such as during the initial dosing phase, change in diet, interaction with other medications, and even secondary to metastatic liver disease. The initial dosing phase presents a specific timeframe of potential toxicity and risk not only due to potentially known aspects such as the patient’s specific comorbidities and diet, but also due to their genetic polymorphisms. Pediatric ingestion may result in warfarin toxicity and can occur due to exploratory ingestion of a child unknowingly taking a pill, as well as through potential Munchausen syndrome by proxy. In addition to the previously discussed methods of intoxication, there have also been reports of warfarin toxicity due to lacing superwarfarins with illicit drugs to prolong euphoric effects.
As mentioned above warfarin was initially used as a pesticide and then formulated as a medication. Resistance was noted though in rats resulting in the development of superwarfarins, which have become common in residences and business as a rodenticide which has resulted in potential human exposure. The superwarfarin labeled substances have become increasingly common with exposures or poisonings jumping from around 5,000 cases in 1988 to over 13,000 cases in 1955. 
In 2014, the Annual Report of the American Association of Poison Control Centers' National Poison Data System reported 1,766 single exposures to prescription warfarin. Of those, 355 ingestions were by Children <6 years old. Unintentional overdose accounted for the vast majority of ingestions of prescription warfarin, accounting for 84%. There were 16 significant clinical events reported however none resulted in death.
In the same year, there were 181 exposures to superwarfarin rodenticides. In contrast to prescription warfarin, a large portion (142) of these ingestions were by children <6 yrs. 170 exposures were deemed unintentional. No major clinical events or deaths were reported.
Warfarin, and superwarfarins, are vitamin K antagonists that primarily act through inhibition of 2,3 vitamin K epoxide reductase and cause a deficiency of active vitamin K. The active vitamin K deficiency leaves coagulation factors II, VII, IX, X, and proteins C and S inactive.
Following oral ingestion, warfarin is quickly absorbed through the gastrointestinal tract (maximal concentration ~ 90 minutes status post ingestion). Despite the quick absorption, an INR response is not noted until factor VII is at approximately 30% of its baseline. In naïve patients, the PT/INR would not be expected to have a rise for 12 hours post ingestion and may continue to rise for several more hours due to ongoing absorption. While chronic overdose resulting in toxicity presents with an elevated PT/INR, that level is expected to remain at or near its maximum value on presentation 
The toxicokinetics varies significantly depending on if warfarin itself was ingested compared to specific superwarfarin agents ingested.
Warfarin toxicity secondary to a chronic overdose presents in a stable state with similar underlying pathophysiology to warfarin dosing. Unfortunately, the toxicokinetics of an acute overdose has not been well described in the literature. Typical warfarin use has a T ½ of 36-42 h, with time to peak effect of 36-72 h, and 2-5 days duration following cessation of the drug. Acute overdose of warfarin has been noted to have a potential delay of PT/INR elevation for 12 hours following ingestion with coagulopathy seen up to 9 days post ingestion.
One difficult aspect of the toxicokinetics is the correlation to clinical signs and complications. Despite being able to follow the INR as a marker of coagulopathy, complications from warfarin use do not routinely occur at one set level. One study of acute overdoses with multiple patients having an INR >10 found only one major bleeding event, no thrombotic events, and no fatal events.
Another difficult aspect in considering the toxicokinetics is the potential for rebound toxicity. There have been case reports of patients being treated for acute warfarin toxicity with Vitamin K with normalization of INR, that present to hospital for readmission >3 days after discharge with bleeding events and a supratherapeutic INR.
Since warfarin is metabolized in the liver by the Cytochrome C-450 system, patients with renal insufficiency are not considered to be at a higher risk of toxicity than the standard population. However, it has been reported that patient with renal insufficiency has required lower doses than the standard population to achieve therapeutic INRs.
In contrast to patients with renal insufficiency or failure, patients with potential hepatic dysfunction can have an unpredictable clinical course. While warfarin has a T ½ of 36 – 42 h, these numbers can be greatly affected by liver disease or alcohol use. Studies have shown that while acute alcohol use may decrease the metabolism of warfarin, chronic alcohol use may cause an increase in the metabolism. Patients with some degree of hepatic dysfunction will have varying rates of warfarin metabolism as well as responses to Vitamin K administration. At this time, there are no set guidelines to predict the metabolism rates or Vitamin K responses in these patients.
As with most drug toxicities, it is important to ask about the type of medication ingested, any concurrent ingestions (including drugs or alcohol) and current medications, the strength of the medications, the timing of ingestion, and intent. Any recent history of trauma, especially to the head, should be noted.
In warfarin toxicity, it is important to ask if the person is currently taking warfarin for an underlying condition, as you may need to consider the risk of reversing the INR. It is also important to ask about any signs or symptoms of abnormal bleeding, such as nosebleeds, dark urine or dark stools. This will be an important piece of information to guide the appropriate clinical treatment. As with any history, be sure to ask about any underlying medical conditions that may alter the clinical course in the setting of warfarin toxicity, specifically asking about alcohol use or potential hepatic disease.
Any potential ingestion or toxicity should undergo a standard primary and secondary survey, including evaluation of vital signs and thorough physical examination. An electrocardiogram, basic metabolic panel, and acetaminophen concentration should be obtained on all toxicology patients with suspected self-harm. Specific evaluation of patients with suspected toxicity is multi-factorial including evaluating for co-ingestions, the potential for pregnancy/complications, targets of the specific substance, and for any possible presenting complaints. 
Specific evaluation of warfarin toxicity should involve evaluation of the patient’s PT, INR, CBC, and BMP with hepatic function, in addition to the standard co-ingestions and a focused evaluation surrounding their symptoms. It is also important to inquire about recent medication changes, dietary or herbal supplements and recent diet changes as all of these factors have been associated with instability in patients who are taking warfarin.
It is important also to investigate how the toxicity occurred, and if focused psychiatric evaluation, or focused evaluation of activities of daily living, is required.
The treatment and management of patients who present with warfarin toxicity can vary greatly depending on a number of clinical factors. Different categories of the patient presentation will be discussed separately. For these recommendations, coagulopathy is defined as INR > 1.4. Warfarin toxicity is defined as INR > 3.0 or >3.5 in a patient with a mechanical heart valve. Unintentional toxicity in patients who are treated with warfarin for an underlying condition (most common presentation).
The following suggests treatment strategies for a patient without significant bleeding (patients with bleeding will be discussed separately):
*It is not recommended that patients without bleeding receive FFP or Prothrombin Complex Concentrate (PCC)
Intentional ingestion of warfarin/superwarfarin in patients not currently on anticoagulation:
Any patient with an intentional ingestion of warfarin/superwarfarin warrants full evaluation regardless of the reported amount ingested. It is recommended that patients undergo measurement of PT/INR and PTT during initial presentation. For acute exposures, patients should receive serial INR assessments every 12-24 hours. If INR remains normalized at 36 hours and there are no signs of bleeding, no further testing is generally necessary. Patients with elevated INR displaying evidence of coagulopathy during evaluation, do not need to be started on vitamin K at unless the INR is greater than 10 or they have evidence of bleeding. There is no reason to prophylactically administer vitamin K and it is associated with increased length of stay and false reassurrance of normalization of INR, as the duration of action of warfarin is much longer than vitamin K.
Activated charcoal can be considered in patients who are awake and alert and present within 1 hour of ingestion.
Patients with acute or chronic toxicity and active bleeding:
Any patient with a coagulopathy due to a vitamin K antagonist and life-threatening bleeding should receive the following treatment:
1. 4-factor Prothrombin Complex Concentrate*, if available or 3-factor PCC and Fresh frozen plasma. If 3 or 4 factor PCC not available, administer FFP alone.
2. Intravenous Vitamin K10mg.
3. Tranexamic acid administration should be considered.
*Prothrombin complex concentrate use has been considered controversial though can normalize an INR. In addition to the potential for fatal thromboembolic events following administration of activated PCC, the overall thromboembolic rate associated with PCC has been noted to be approximately 0.9%.
**Plasma transfusion has been noted to be used in patients with intracranial hemorrhage who require immediate reversal of warfarin coagulopathies. Specifically, 15-30 ml/kg has been noted to restore clotting factor levels to a baseline of 30-50%.
Unintentional ingestion in patients who are not chronically anticoagulated, including pediatrics:
Warfarin toxicity is quite common and is best managed by an interprofessional team. Clinicians need to educate the patient on the need to closely monitor their diet and dose. Clinicians including pharmacists also have the responsibility of ensuring that the patient is on no other medications that can interact adversely with warfarin. Nursing can also contribute to uncovering risks during patient visits and report concerns to the prescriber or consult with the pharmacist. For patients deemed at high risk for warfarin toxicity, switching to the newer oral anticoagulants may be an option.
Warfarin toxicity usually requires admission and increases the costs of healthcare. The outcomes depend on the presence of bleeding in the brain; those with CNS bleed usually have poor outcomes. (Level V)
|||Carpenter M,Berry H,Pelletier AL, Clinically Relevant Drug-Drug Interactions in Primary Care. American family physician. 2019 May 1; [PubMed PMID: 31038898]|
|||Mourad AP,Aslani P,D'Souza M,Brieger D, The acceptability of a direct oral anticoagulant monitoring regimen among patients with atrial fibrillation: a pilot study. International journal of clinical pharmacy. 2019 Apr 17; [PubMed PMID: 31016680]|
|||Radhakrishnan S, A note on wildlife poisoning cases from Kerala, South India. European journal of wildlife research. 2018 Sep 22; [PubMed PMID: 30820194]|
|||Kalinin S,Marangoni N,Kowal K,Dey A,Lis K,Brodsky S,van Breemen R,Hauck Z,Ripper R,Rubinstein I,Weinberg G,Feinstein DL, The Long-Lasting Rodenticide Brodifacoum Induces Neuropathology in Adult Male Rats. Toxicological sciences : an official journal of the Society of Toxicology. 2017 Sep 1; [PubMed PMID: 28903499]|
|||Schwalfenberg GK, Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health. Journal of nutrition and metabolism. 2017; [PubMed PMID: 28698808]|
|||Vu TT,Gooderham M, Adverse Drug Reactions and Cutaneous Manifestations Associated With Anticoagulation. Journal of cutaneous medicine and surgery. 2017 Nov/Dec; [PubMed PMID: 28639463]|
|||Conway SE,Hwang AY,Ponte CD,Gums JG, Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know. Pharmacotherapy. 2017 Feb; [PubMed PMID: 27983747]|
|||Hersh EV,Moore PA, Three Serious Drug Interactions that Every Dentist Should Know About. Compendium of continuing education in dentistry (Jamesburg, N.J. : 1995). 2015 Jun; [PubMed PMID: 26053779]|
|||Najmanová I,Doseděl M,Hrdina R,Anzenbacher P,Filipský T,Říha M,Mladěnka P, Cardiovascular effects of coumarins besides their antioxidant activity. Current topics in medicinal chemistry. 2015; [PubMed PMID: 25697565]|
|||Alquwaizani M,Buckley L,Adams C,Fanikos J, Anticoagulants: A Review of the Pharmacology, Dosing, and Complications. Current emergency and hospital medicine reports. 2013 Jun; [PubMed PMID: 23687625]|
|||Berling I,Mostafa A,Grice JE,Roberts MS,Isbister GK, Warfarin Poisoning with Delayed Rebound Toxicity. The Journal of emergency medicine. 2017 Feb; [PubMed PMID: 27838137]|
|||Toyoda K, Antithrombotic therapy for pregnant women. Neurologia medico-chirurgica. 2013; [PubMed PMID: 23979047]|
|||Shearer MJ, Vitamin K in parenteral nutrition. Gastroenterology. 2009 Nov; [PubMed PMID: 19874942]|
|||Choumane NS,Malaeb DN,Malaeb B,Hallit S, A multicenter, prospective study evaluating the impact of the clinical pharmacist-physician counselling on warfarin therapy management in Lebanon. BMC health services research. 2018 Feb 1; [PubMed PMID: 29391010]|
|||Jorgensen AL,Al-Zubiedi S,Zhang JE,Keniry A,Hanson A,Hughes DA,Eker Dv,Stevens L,Hawkins K,Toh CH,Kamali F,Daly AK,Fitzmaurice D,Coffey A,Williamson PR,Park BK,Deloukas P,Pirmohamed M, Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenetics and genomics. 2009 Oct; [PubMed PMID: 19752777]|